1. Field of the Invention
This invention relates generally to cancer therapy, and more particularly to cancer therapy using DPD inhibitors in combination with 5-FU and/or 5-FU prodrugs.
2. Description of the Related Art
5-Fluorouracil (5-FU) has been clinically used to treat solid tumors in cancer patients for over three decades (Ansfield et al., Cancer 39: 34-40, 1977; Grem et al., Cancer Treat Rep 71: 1249-1264, 1987; Chabner et al., Cancer, Principles and Practice of Oncology, 2nd Ed, pp 287-328 Philadelphia, Pa.: J B Lippincott Co, 1985). 5-FU must be activated by metabolic conversion to fraudulent uridine nucleotides (e.g., FUMP, FUDP, FUTP) and deoxyuridine nucleotides (e.g., FdUMP, FdUDP, FdUTP) that interfere with DNA synthesis and RNA functions (reviewed in Meyers, Pharmacol Rev, 33: 1-15, 1981; Dasher et al., Pharmac Ther 48: 189-222, 1990). Because 5-FU differs from uracil, its natural counterpart, by only a fluorine substitution in the 5-position, it is readily activated in cancer patients. Unfortunately, its structural similarity to uracil also accounts for its rapid and extensive conversion to breakdown products that have no antitumor activity. This metabolic process is referred to as inactivation. 5-FU is rapidly inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD: EC 1312, uracil reductase) (Meyers, Pharmacol Rev, 33: 1-15, 1981; Dasher et al., Pharmac Ther 48: 189-222, 1990). Therefore, the antitumor efficacy of 5-FU for treating cancer relies on the delicate balance between metabolic conversion to antitumor nucleotides (activation) and metabolic conversion to useless metabolites (inactivation).
Furthermore, several clinical issues arise due to the metabolic inactivation of 5-FU. First, because the levels of DPD vary among individuals (Fleming et al., Cancer Res 52: 2899-2902, 1992; Grem et al., Cancer Chemother Pharmacol 40: 117-125, 1997) and within individuals during the course of a day (Grem et al., Cancer Chemother Pharmacol 40: 117-125, 1997; Harris et al., Cancer Res 50: 197-201, 1990; Petit et al., Cancer Res 48: 1676-1679, 1988), the systemic levels of 5-FU produced from a given dose vary greatly and therefore render efficacy and toxicity highly unpredictable. At the extreme, patients genetically deficient in DPD experience severe and sometimes fatal toxicity when treated with ‘standard’ therapeutic doses of 5-FU (reviewed in Morrison et al., Oncol Nurs Forum 24: 83-88, 1997). Second, variable levels of gastrointestinal DPD (Ho et al., Anticancer Res 6: 781-784, 1986; Naguib et al., Cancer Res 45: 5405-5412, 1985; Spector et al., Biochem Pharmacol 46: 2243-2248, 1993) create highly variable absorption of orally dosed 5-FU (Christophidis et al., Clin Pharmacokinetics 3: 330-336, 1978; Cohen et al., Cancer Chemother Rep 58: 723-731, 1974; Finch et al., Br J Clin Pharmacol 7: 613-617, 1979) and therefore can result in unpredictable plasma levels of drug and produce undesirable toxicity or inadequate efficacy. Third, tumors containing high levels of DPD are less likely to respond to 5-FU-treatment (Etienne et al., J Clin Oncol 13: 1663-1670, 1995; Fischel et al., Clin Cancer Res 1: 991-996, 1995). Finally, the breakdown products of 5-FU may produce neurotoxicity (Okeda et al., Acta Neuropathol 81: 66-73, 1990; Koenig et al. Arch Neurol 23: 155-160, 1970), cardiotoxicity (et al., Lancet 337: 560, 1991; Lemaire et al., Br J Cancer 66: 119-127, 1992), palmer-plantarerythrodysaesthesia (hand-foot syndrome) (Hohneker, Oncology 12: 52-56, 1998), and GI toxicity (Spector et al., Cancer Res 55: 1239-1241, 1995) and appear to interfere with the antitumor activity (Spector et al., Cancer Res 55: 1239-1241, 1995; Cao, et al., Pharmacol 59: 953-960, 2000).
DPD is a ubiquitous enzyme that is the first and the rate-limiting step in the degradation (inactivation) of 5-FU. Studies have shown that inhibition of DPD prolongs the half-life of 5-FU in plasma. Several DPD inhibitors have been studied, including those that irreversibly inactivate DPD as well as those that reversibly inhibit DPD.
5-Ethynyluracil, also referred to as eniluracil, is an example of a DPD inhibitor that is an irreversible inactivator of DPD that reduces or eliminates the metabolic inactivation of 5-FU (for reviews see Spector et al., Drugs of The Future 19: 565-571, 1994; Paff et al., Invest. New Drugs: 18,365-371 (2000)). Due to the structural similarity between eniluracil and 5-FU, eniluracil is a substrate for DPD. As DPD attempts to break down eniluracil, the latter is converted to a highly reactive compound that irreversibly binds to DPD and thereby inactivates the enzyme. Thus, in the presence of very low amounts of eniluracil, DPD is destroyed and is no longer capable of inactivating 5-FU. Active DPD only reappears in such patients as a result of de novo DPD enzyme synthesis over a course of days.
Eniluracil has been tested in Phase I clinical trials in cancer patients (reviewed in Levin et al., Invest New Drugs 18:383-90, 2000; Baker et al., J Clin Oncol 18: 915-926 2000; Schilsky et al., J Clin Oncol 4:1450-7, 1998). It very potently eliminated DPD activity without causing toxicity. A dose of 0.74 mg/m2 (about 1 mg total) eliminated greater than 90% of all DPD for prolonged periods. In fact, 24 hours after one dose of eniluracil, the level of DPD was only 3% of the predose level. The elimination half-life of 5-FU was increased from about 10 minutes to 3.5 hours by one dose of eniluracil. A dose of 3.7 mg/m2 eniluracil increased the half-life of 5-FU to 4.5 hours. Higher doses added no apparent benefit.
Eniluracil has also been orally administered in Phase II and Phase III clinical trials (reviewed in Levin et al., Invest New Drugs 18:383-90, 2000; Schilsky et al., J Clin Oncol: 20:1519-26, 2002). Two dosing regimens were used in these trials. In the ‘5-day schedule’, eniluracil was administered at a fixed dose of 50 mg per day on day-1 through day-7. 5-FU was dosed at approximately 20 mg/m2 on day-2 through day-6 after the dose of eniluracil. In the ‘28-day schedule’, eniluracil and 5-FU were co-administered in a fixed ratio of ten eniluracil to one 5-FU b.i.d. (twice daily) for 28 days. The dose of 5-FU was approximately 1 mg/m2. Eniluracil abrogated the 5-FU-associated hand-foot syndrome toxicity, enabled 5-FU to be safely dosed orally, and resulted in highly predictable 5-FU plasma levels. However, the antitumor activity of these regimens was unfortunately disappointing. In two multicenter Phase III studies using the 28-day eniluracil regimen for colorectal cancer, patients receiving eniluracil and 5-FU tended to have less antitumor activity than those treated with the standard 5-FU regimen without eniluracil (Schilsky et al., J Clin Oncol: 20:1519-26, 2002).
Thus, there remains an important and unmet need in the art for identifying optimal dosing and administration schedules for DPD inhibitors used in combination with 5-FU and 5-FU prodrugs in order to maximize the antitumor efficacy and therapeutic index of 5-FU and 5-FU prodrugs, to improve the predictability of dosing and to enable 5-FU and 5-FU prodrugs to be effectively dosed by oral administration. The present invention fulfills these needs and offers other related advantages.